Burden, risk factors and outcomes associated with adequately treated hypothyroidism in a population-based cohort of pregnant women from North India

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There is limited data on population-based prevalence, risk factors and outcomes associated with treatment of hypothyroidism in early pregnancy. We conducted analysis on data from an urban and peri-urban low to mid socioeconomic population-based cohort of pregnant women in North Delhi, India to ascertain the burden, risk factors and impact of treatment, on adverse pregnancy outcomes- low birth weight, prematurity, small for gestational age and stillbirth. Methods This is an observational study embedded within the intervention group of the Women and Infants Integrated Interventions for Growth Study, an individually randomized factorial design trial. Thyroid stimulating hormone was tested in 2317 women in early (9-13 weeks) pregnancy, and thyroxin replacement started in those found hypothyroid (TSH ≥2.5mIU/mL). Univariable and multivariable generalized linear model with binomial family and log link were performed to ascertain risk factors associated with hypothyroidism and association between hypothyroidism and adverse pregnancy outcomes. Results Of 2317 women, 29.2% (95% CI: 27.4 to 31.1) had hypothyroidism and were started on thyroxin replacement with close monitoring. Overweight or obesity was associated with increased risk (adjusted RR 1.29, 95% CI 1.10 to 1.51), while higher hemoglobin concentration was protective (adjusted RR 0.93, 95% CI 0.88 to 0.98 for each g/dL) for hypothyroidism. Women with hypothyroidism, received appropriate treatment did not have an increase in adverse pregnancy outcomes. Conclusions Almost a third of women from low to mid socio-economic population had hypothyroidism in early pregnancy, more so if anemic and overweight or obese. With early screening and adequate replacement, adverse pregnancy outcomes may be avoided. These findings highlight the need in early pregnancy for universal TSH screening and adequate treatment of hypothyroidism; as well as for attempts to reduce pre and peri-conception overweight, obesity and anemia. Clinical Trial registration: Clinical trial registration of Women and Infants Integrated Interventions for Growth Study Clinical Trial Registry – India, #CTRI/2017/06/008908; Registered on: 23/06/2017, (http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19339&EncHid=&userName=society%20for%20applied%20studies) Hypothyroidism Low birth weight Preterm Small for gestational age Background The thyroid gland plays a key role in pregnancy homeostasis and metabolic adaptations important for fetal development, as well as supply of energy to the mother. It undergoes adaptive changes to meet the increased demand during pregnancy, and women with low reserves during preconception frequently enter pregnancy in hypothyroid state. Hypothyroidism is the commonest endocrine disorder of pregnancy, and if not adequately treated, can result in adverse pregnancy outcomes- growth restriction, prematurity, low birth weight (LBW) and stillbirth ( 1 , 2 ). However, the symptoms are nonspecific and insidious; hence, diagnosis is usually missed or made much later due to delayed reporting of pregnancy ( 3 ). Globally, hypothyroidism affects 3–5% of all pregnant women, however, the prevalence is higher in Asian countries ( 4 ). In a Chinese study of 2899 pregnant women, the prevalence of hypothyroidism (TSH > 3.93 mIU/L) in the first trimester was 10.9% ( 5 ). Yadav et al, in a meta-analysis of observational studies, reported a pooled prevalence of 11.01% in pregnant women in India ( 6 ), however, only two of the 54 studies were community based, and the cut off levels of TSH used were not uniform, varying from 2.3–4.5 mIU/mL in all three trimesters of pregnancy. Data from secondary and tertiary hospital across nine states in India showed 13.1% prevalence in the first trimester, with a TSH cutoff of 4.5 mIU/mL ( 7 ). The thyroid stimulating hormone (TSH) assay is a simple, sensitive, commonly used screening tool for thyroid dysfunction in pregnancy but is limited by lack of uniformly accepted reference ranges which vary according to laboratory reference levels, type of assay, and population heterogeneity. The new third generation assays have high functional sensitivity as recommended by the American Thyroid Association (ATA) and are a good tool for diagnosing primary thyroid dysfunction ( 8 ). The National Guidelines in India (2014) recommend treatment aimed at maintenance of TSH < 2.5 mIU/mL in the first trimester and < 3 mIU/mL in the second and third trimester of pregnancy, similar to the guidelines of the Endocrine Society ( 9 , 10 ). The ATA 2017 recommends 4 mIU/mL as the upper limit of normal, in the absence of population specific ranges ( 11 ). A systematic review of normative values of trimester specific thyroid function in Indian women concluded that TSH cut offs of up to 5–6 mIU/mL, similar to the pre-pregnancy stage, should be used in the first trimester of pregnancy, although it was limited by the fact that no outcomes were included ( 12 ). There are limited data on population-based prevalence, risk factors and adverse outcomes of hypothyroidism in pregnancy, particularly in low to mid socio-economic populations. We conducted an analysis of data from a population-based cohort of urban and peri-urban low-mid socioeconomic strata neighborhoods of Delhi to determine the prevalence of hypothyroidism in pregnancy, its risk factors, and impact of replacement on adverse pregnancy outcomes LBW, prematurity, small for gestational age (SGA), and stillbirth. Methods Study Design, setting and participants This is an observational study embedded within the intervention group of the Women and Infants Integrated Interventions for Growth Study (WINGS), conducted in urban and peri-urban low-to-mid-socioeconomic neighborhoods in south Delhi, India. A summary of WINGS is provided below; the details of methods have been previously published ( 13 ). Briefly, 13,500, eligible women aged 18–30 years were identified through a door-to-door survey. Women who provided written consent to participate in the study were enrolled (first randomization) to receive pre and peri-conception interventions or routine care and followed up until their pregnancies were confirmed, or for 18 months after enrollment. At confirmation of pregnancy by ultrasonography, after obtaining written consent a second randomization was done wherein pregnant women received enhanced pregnancy and early childhood care or routine care. Study Description Pregnant women in the intervention group received at least eight antenatal care visits. Body mass index (BMI) was measured, and a non-fasting serum TSH and hemoglobin tested at the time of confirmation of pregnancy. Women with TSH ≥ 2.5 mIU/mL were labelled as hypothyroid and were managed with replacement doses of levothyroxine, after a thorough history and clinical assessment as per the National Guidelines ( 9 ). TSH levels were repeated monthly, and thyroxine dose titrated till TSH stabilized to normal pregnancy reference levels ( 9 ). Once normalized, a repeat TSH for monitoring, was done twice in the second trimester, and once in the late third trimester which amounted to an approximate five to six repeat assays of TSH in pregnancy. Close follow up was done by study team workers who made weekly home visits to ensure compliance, and progress was monitored using electronic trackers. Those with uncontrolled TSH and TSH < 0.1 mIU/mL were referred to the endocrinology clinic of the collaborating government tertiary care hospital (Safdarjung Hospital, New Delhi, India). Laboratory Analysis Blood samples for TSH assay were collected in serum separator tubes (SST), transported in cool boxes (4˚to 8˚C) to the field laboratory where centrifugation was done at ~ 450 × g at room temperature for 10 minutes, to separate serum and then transported to a NABH accredited study laboratory (Oncquest Laboratory) maintaining cold chain. Serum TSH was analyzed using the Architect (Ci 8200 Abbott-Architect) TSH assay, a two-step immunoassay using chemiluminescent microparticle immunoassay (CMIA) technology with an inter-assay coefficient of variation (CV) of 20% which meets the requirements of a of third generation TSH assay. The Architect TSH assay has an analytical sensitivity of < 0.01 µIU/mL ( 14 ). Statistical analysis Sociodemographic characteristics were reported as mean (SD), or proportions, as appropriate. We calculated incidence (95% confidence interval: CI) of hypothyroidism occurring at the time of pregnancy confirmation. Univariable and multivariable generalized linear model with binomial family and log link were performed to ascertain risk factors associated with hypothyroidism. We calculated unadjusted and adjusted risk ratios (RR) and their 95% CI for the association between hypothyroidism and adverse pregnancy outcomes (LBW, SGA, preterm birth, spontaneous preterm birth, stillbirth) using generalized linear model with binomial family and log link. The candidate variables were related to socio-demographic and nutritional status of the women; continuous (maternal age, hemoglobin and glycosylated hemoglobin (HbA1c) levels at the time of confirmation of pregnancy), and categorical (height (< 150 and ≥ 150 cm), years of schooling < 12 and ≥ 12 years), early pregnancy (gestational age ≤ 20 weeks), BMI, religion (Hindu and others), type of family (extended or joint, and nuclear), family with a below-poverty-line card, and family covered by health insurance scheme. All statistical analyses were performed using STATA version 16 (StataCorp, College Station, TX, USA). Results In this study 2317 women were followed up from pregnancy till delivery. The median (IQR) of gestational age at the time of recruitment was 9.5 (9.1–11.0) weeks. Socioeconomic and clinical characteristics of enrolled women prior to pregnancy are shown in Table 1 . The study population was relatively young with a mean (SD) age of 23.8 (3.1) years, about half of them had education more than 12 years. Height was less than 150 cm in 34.1%; mean (SD) BMI was 22.2 (3.9) kg/m 2 ; with dual burden of malnutrition: 15% women underweight and 24% women overweight or obese (Table 1 ). Table 1 Sociodemographic characteristics of pregnant women Characteristics of pregnant women Euthyroid n = 1640 Hypothyroid n = 677 Age (years), mean (SD) 23.7 (3.1) 24.0 (3.0) Height (cm), mean (SD) 152.4 (5.5) 152.2 (5.8) Height < 150 cm 543 (33.1) 246 (36.3) Schooling ≥ 12 year 837 (51.0) 332 (49.0) Homemaker 1562 (95.2) 644 (95.1) Early pregnancy BMI, mean (SD) Underweight (< 18.5 kg/m 2 ) Overweight or obesity (≥ 25 kg/m 2 ) 22.2 (3.9) 258 (15.7) 364 (22.2) 22.9 (4.1) 91 (13.4) 192 (28.4) Hindu 1340 (81.7) 566 (83.6) Family had a below poverty line card 55 (3.4) 23 (3.4) Family covered by a health insurance scheme 170 (10.4) 78 (11.5) Joint or extended family* 1079 (65.8) 458 (67.6) All values are numbers (percentages) unless stated otherwise * Joint or extended family: Adult relatives other than the enrolled woman’s husband and children living together in a household Table 2 shows the thyroid status of pregnant women at the time of confirmation of pregnancy, with 29.2% (95% CI: 27.4 to 31.1) having hypothyroidism (TSH ≥ 2.5 mIU/mL). Table 2 Thyroid status at the time of confirmation of pregnancy TSH level n(%) 95% CI Mean (SD) Median (IQR) n = 2317 TSH < 0.1 mIU/mL 64 (2.8) 2.1 to 3.5 0.04 (0.02) 0.04 (0.04 to 0.05) TSH 0.1 to < 2.5 mIU/mL 1576 (68.0) 66.1 to 69.9 1.3 (0.6) 1.3 (0.8 to 1.8) TSH ≥ 2.5 to < 10 mIU/mL 652 (28.1) 26.3 to 30.0 4.0 (1.4) 3.6 (3.0 to 4.6) TSH ≥ 10 mIU/mL 25 (1.1) 0.6 to 1.6 51.9 (124.2) 15.4 (13.0 to 33.6) Table 3 shows the association between socioeconomic and clinical characteristics of women with hypothyroidism. Overweight or obesity in early pregnancy was associated with increased risk (adjusted RR 1.29, 95% CI 1.10 to 1.51) of hypothyroidism. Hemoglobin concentration was a protective factor (adjusted RR 0.93, 95% CI 0.88 to 0.98 for each g/dL) for hypothyroidism. Table 3 Potential risk factors for hypothyroidism in enrolled women Risk factors for hypothyroidism Unadjusted RR (95% CI) Adjusted RR (95% CI) Age (per 1 year) 1.02 (1.00 to 1.04); p = 0.046 1.01 (0.99 to 1.04); p = 0.249 Height (< 150 cm) 1.10 (0.97 to 1.26); p = 0.134 1.07 (0.92 to 1.23); p = 0.372 Schooling ≥ 12 year 0.94 (0.83 to 1.07); p = 0.382 0.93 (0.80 to 1.07); p = 0.307 Homemaker 0.98 (0.73 to 1.31); p = 0.903 1.08 (0.76 to 1.53); p = 0.670 Joint or extended family 1.06 (0.93 to 1.22); p = 0.391 1.10 (0.95 to 1.28); p = 0.231 Family had below-poverty-line card 1.01 (0.72 to 1.43); p = 0.958 1.00 (0.69 to 1.46); p = 0.990 Family covered by health insurance scheme 1.10 (0.90 to 1.32); p = 0.407 1.06 (0.85 to 1.32); p = 0.577 Hindu religion 1.10 (0.92 to 1.31); p = 0.283 1.10 (0.91 to 1.33); p = 0.341 Early pregnancy BMI Normal BMI Underweight (< 18.5 kg/m 2 ) Overweight or obesity (≥ 25 kg/m 2 ) Reference 0.93 (0.77 to 1.13); p = 0.497 1.24 (1.07 to 1.43); p = 0.003 Reference 0.97 (0.78 to 1.20); p = 0.783 1.29 (1.10 to 1.51); p = 0.002 Hemoglobin at pregnancy confirmation (per 1 percentage) 0.96 (0.91 to 1.01): p = 0.114 0.93 (0.88 to 0.98): p = 0.009 HbA1c (%) at pregnancy confirmation (per 1 percentage) 0.96 (0.80 to 1.15); p = 0.644 0.92 (0.77 to 1.10); p = 0.363 Table 4 shows the association of hypothyroidism with adverse pregnancy outcomes where management of hypothyroidism was supported by the research team. We found no significant association of hypothyroidism with LBW, SGA, preterm, spontaneous preterm birth and stillbirth. Table 4 Association between hypothyroidism and adverse pregnancy outcomes Outcome No hypothyroid n(%) Hypothyroid n(%) Unadjusted RR (95% CI) Adjusted RR* (95% CI) Low birth weight n = 1388 326 (23.5) n = 560 142 (25.4) 1.08 (0.91 to 1.28) 1.08 (0.91 to 1.28) Small for gestational age n = 1382 370 (26.8) n = 554 176 (31.8) 1.19 (1.02 to 1.38) 1.20 (1.00 to 1.44) Preterm birth n = 1592 202 (12.7) n = 649 76 (11.7) 0.92 (0.72 to 1.18) 0.90 (0.71 to 1.16) Spontaneous preterm birth n = 1592 122 (7.7) n = 649 38 (5.9) 0.76 (0.54 to 1.10) 0.76 (0.54 to 1.09) Stillbirth n = 1603 22 (1.4) n = 659 14 (2.1) 1.55 (0.80 to 3.01) 1.53 (0.79 to 2.98) *adjusted for maternal age, height, years of schooling, early pregnancy (gestational age ≤ 20 weeks), BMI Discussion The main findings of this study were the high prevalence of hypothyroidism in early pregnancy, occurring in 29.2% of the population-based cohort and that treating hypothyroidism early and adequately did not no increase in adverse outcomes (stillbirth, preterm birth, LBW, SGA). Anemia, overweight and obesity in early pregnancy were identified as risk factors for hypothyroidism. A wide disparity in the prevalence of hypothyroidism in pregnancy has been reported in previous studies in India. A hospital-based study from nine states of India reported 15% prevalence of hypothyroidism using TSH levels of > 4.5 mIU/mL and of 44.3% using a cut off level of > 2.5 mIU/mL in first trimester ( 7 ). A meta-analysis of observational studies with varying gestational ages and TSH cut off values found the prevalence of hypothyroidism in pregnancy to be 11% ( 6 ). A prospective observational study from central part of India found hypothyroidism in 9.1% in the third trimester of pregnancy using a cut off of TSH > 5 mIU/mL. Similar to our study, Bein et al in a systemic review and metaanlysis reported a decrease in risk of pregnancy loss and neonatal death with treatment of subclinical hypothyroidism ( 15 ). Similar to our finding, a study from southern part of India showed overweight or obesity was a risk factor for hypothyroidism in early pregnancy, and high maternal TSH is associated with obesity and higher weight gain ( 16 , 17 ). The association of obesity and overweight with adverse outcomes is well documented including a recent systemic review and metaanalysis ( 18 , 19 ). Similarly, our finding of a higher hemoglobin level being protective was echoed in a systemic review and meta analysis which found that iron deficiency adversely affects thyroid function and autoimmunity in pregnant women ( 20 ). Also, a study from China found that proportion of hypothyroidism was higher in women with mild anemia in the first trimester than in women with no anemia ( 21 ). The strengths of our study are that it is population-based; the socioeconomic strata is low to middle income, which represents the average Indian population; serum TSH was used for thyroid status assessment, which is feasible as a screening test in settings like India where pregnant women may not return after the first visit due to economic reasons, lack of easy accessibility to the health center, etc., and the evidence that early identification and adequate treatment, reduced the risk of adverse pregnancy outcomes. The limitations of our study are that we did not test for other thyroid hormones (T4, T3, Free T4, Free T3), so we could not distinguish subclinical from overt hypothyroidism; nor did we test for thyroid antibodies, which could have helped us detect “at risk” pregnancies. This study has important implications for health care of women of the reproductive age group. First, the high burden of hypothyroidism in early pregnancy and the prevention of adverse pregnancy outcomes with early management highlights the need for early detection and treatment in antenatal care programs. Secondly, preventive interventions could be introduced preconceptionally to reduce risk factors, like obesity and overweight, and low hemoglobin levels. Conclusion Almost a third of women from a mid-low socio-economic population may be at risk for developing hypothyroidism in early pregnancy. Anemia, being overweight or obese may increase the risk. Ensuring universal TSH screening in early pregnancy, and adequate treatment if hypothyroidism is detected, would serve to improve pregnancy outcomes. Reducing pre and periconception obesity and anemia could help reduce the risk of hypothyroidism. Abbreviations CI: confidence interval; ARR: adjusted relative risk; BMI: body mass index; LBW: low birth weight; SGA: small for gestational age; TSH: thyroid stimulating hormone; WINGS: women and Infants integrated interventions for growth study; ATA: american thyroid association ; SST: serum separator tubes; CMIA: chemiluminescent microparticle immunoassay; CV: coefficient of variation; RR: risk ratios Declarations Ethics approval and consent to participate The Ethics Review Committees of the Society for Applied Studies, Vardhman Mahavir Medical College and Safdarjung Hospital, and the World Health Organization, Geneva approved the study conducted with the relevant guidelines and regulations (e.g. Declaration of Helsinki). Written informed consent was obtained from the study participants. Consent for publication Not Applicable. Availability of data and materials The dataset analyzed during the current study are not publicly available because Society for Applied Studies, India is a collaborator in the Healthy Birth, Growth, and Development Knowledge Integration (HBGDKi) initiative launched by the Bill & Melinda Gates Foundation. However, individual requests can be considered on a case-by-case basis. The request for data along with the detailed proposal describing the intended scientific question (s) to be addressed, should be submitted to Dr. Sunita Taneja ( [email protected] ). Competing interests The authors declare that they have no competing interests. Funding The main trial was funded by the Biotechnology Industry Research Assistance Council (BIRAC), Department of Biotechnology, Government of India under the Grand Challenges India- All Children Thriving Initiative (GCIACT Ref No: BIRAC/GCI/0085/03/14-ACT) and the Bill & Melinda Gates Foundation, USA (Grant ID #OPP1191052). The funding agencies did not play any role in study design and are neither involved in nor have any influence over the collection, analyses or interpretation of data. Authors’ contributions ND, RaC, NB, AV, ST were involved in conceptualizing the research questions, data file preparation, statistical analysis, data interpretation, writing and editing of manuscript. RiC, PM, RD, JK critically revised the manuscript for relevant intellectual content. All authors contributed to preparation and finalization of the manuscript and have read and approved the final manuscript. Acknowledgements We The Society for Applied Studies gratefully acknowledges the contribution and support of the mothers, their families and others in the community. We acknowledge the core support provided by the Department of Maternal, Newborn, Child and Adolescent Health, World Health Organization, Geneva (WHO Collaborating Centre IND-158). References Mahadik K, Choudhary P, Roy PK. Study of thyroid function in pregnancy, its feto-maternal outcome; a prospective observational study. BMC pregnancy and childbirth. 2020;20(1):769. Cunningham FG, Leveno KJ, Bloom SL, Dashe JS, Hoffman BL, Casey BM, et al. Overview of Obstetrics. Williams Obstetrics, 25e. New York, NY: McGraw-Hill Education; 2018. Warri D, George A. Perceptions of pregnant women of reasons for late initiation of antenatal care: a qualitative interview study. BMC pregnancy and childbirth. 2020;20(1):70. Teng W, Shan Z, Patil-Sisodia K, Cooper DS. Hypothyroidism in pregnancy. The lancet Diabetes & endocrinology. 2013;1(3):228–37. Wang W, Teng W, Shan Z, Wang S, Li J, Zhu L, et al. The prevalence of thyroid disorders during early pregnancy in China: the benefits of universal screening in the first trimester of pregnancy. European journal of endocrinology. 2011;164(2):263–8. Yadav V, Dabar D, Goel AD, Bairwa M, Sood A, Prasad P, et al. Prevalence of Hypothyroidism in Pregnant Women in India: A Meta-Analysis of Observational Studies. Journal of thyroid research. 2021;2021:5515831. Dhanwal DK, Bajaj S, Rajput R, Subramaniam KA, Chowdhury S, Bhandari R, et al. Prevalence of hypothyroidism in pregnancy: An epidemiological study from 11 cities in 9 states of India. Indian journal of endocrinology and metabolism. 2016;20(3):387–90. Aw T, Sickan J, Du S, Li J, Janel H. Reference Intervals for TSH on the Architect Analyser Based on the National Academy of Clinical Biochemistry (NACB) Guidelines Derived from Healthy Multi-Ethnic Asians Attending a Community Health Fair. Int Arch Endocrinol Clin Res. 2019;5:015. India MHDMoHFWGo. National Guidelines for Screening of Hypothyroidism during Pregnancy, India. 2014. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2012;97(8):2543–65. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid: official journal of the American Thyroid Association. 2017;27(3):315–89. Kannan S, Mahadevan S, Sigamani A. A Systematic Review on Normative Values of Trimester-specific Thyroid Function Tests in Indian Women. Indian journal of endocrinology and metabolism. 2018;22(1):7–12. Taneja S, Chowdhury R, Dhabhai N, Mazumder S, Upadhyay RP, Sharma S, et al. Impact of an integrated nutrition, health, water sanitation and hygiene, psychosocial care and support intervention package delivered during the pre- and peri-conception period and/or during pregnancy and early childhood on linear growth of infants in the first two years of life, birth outcomes and nutritional status of mothers: study protocol of a factorial, individually randomized controlled trial in India. Trials. 2020;21(1):127. Sarkar R. TSH Comparison Between Chemiluminescence (Architect) and Electrochemiluminescence (Cobas) Immunoassays: An Indian Population Perspective. Indian journal of clinical biochemistry: IJCB. 2014;29(2):189–95. Bein M, Yu OHY, Grandi SM, Frati FYE, Kandil I, Filion KB. Levothyroxine and the risk of adverse pregnancy outcomes in women with subclinical hypothyroidism: a systematic review and meta-analysis. BMC endocrine disorders. 2021;21(1):34. Fallatah AM, Hasanain A, Babatin H, Nassibi KM, Thigah S, Abduljabbar HS. Pregnancy Outcomes among Obese Pregnant Women with Hypothyroidism: Medical Record Review of a Single Tertiary Center in Saudi Arabia. Cureus. 2020;12(2):e6938. Collares FM, Korevaar TIM, Hofman A, Steegers EAP, Peeters RP, Jaddoe VWV, et al. Maternal thyroid function, prepregnancy obesity and gestational weight gain-The Generation R Study: A prospective cohort study. Clinical endocrinology. 2017;87(6):799–806. Song RH, Wang B, Yao QM, Li Q, Jia X, Zhang JA. The Impact of Obesity on Thyroid Autoimmunity and Dysfunction: A Systematic Review and Meta-Analysis. Frontiers in immunology. 2019;10:2349. Pillai NS, Bennett J. Prevalence of hypothyroidism amongst pregnant women: a study done in rural set up. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2018;7(4):1586–92. Luo J, Wang X, Yuan L, Guo L. Iron Deficiency, a Risk Factor of Thyroid Disorders in Reproductive-Age and Pregnant Women: A Systematic Review and Meta-Analysis. Frontiers in endocrinology. 2021;12:629831. Nie GY, Wang R, Liu P, Li M, Sun DJ. Mild Anemia May Affect Thyroid Function in Pregnant Chinese Women During the First Trimester. Frontiers in endocrinology. 2021;12:772917. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Chowdhury","email":"data:image/png;base64,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","orcid":"","institution":"Society for Applied Studies","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ranadip","middleName":"","lastName":"Chowdhury","suffix":""},{"id":114268883,"identity":"0f78700b-58b8-46ef-83d5-c9620378e64f","order_by":2,"name":"Anju Virmani","email":"","orcid":"","institution":"Max Smart Superspeciality Hospital, Rainbow 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Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Pratima","middleName":"","lastName":"Mittal","suffix":""},{"id":114268887,"identity":"f1805d4a-f1c6-4c96-b28f-a314c8eac02e","order_by":6,"name":"Rupali Dewan","email":"","orcid":"","institution":"Vardhaman Mahavir Medical College and Safdarjung Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rupali","middleName":"","lastName":"Dewan","suffix":""},{"id":114268888,"identity":"4849a291-75f9-49ba-b47c-f81f52399ed9","order_by":7,"name":"Arjun Dang","email":"","orcid":"","institution":"Dr Dangs Lab","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Arjun","middleName":"","lastName":"Dang","suffix":""},{"id":114268889,"identity":"14270c09-a529-4935-b131-cca6136e0a59","order_by":8,"name":"Jasmine Kaur","email":"","orcid":"","institution":"Society for Applied Studies","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jasmine","middleName":"","lastName":"Kaur","suffix":""},{"id":114268890,"identity":"d9648e50-802d-4758-8350-f3d1933dd87b","order_by":9,"name":"Nita Bhandari","email":"","orcid":"","institution":"Society for Applied Studies","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Nita","middleName":"","lastName":"Bhandari","suffix":""}],"badges":[],"createdAt":"2022-06-07 11:44:30","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1733985/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1733985/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":32235141,"identity":"233da41e-4c1d-4aec-8dcd-523045c76476","added_by":"auto","created_at":"2023-01-30 22:29:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":337951,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1733985/v1/9e4bdbb5-a812-420d-a87c-d14ec6e53c0a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Burden, risk factors and outcomes associated with adequately treated hypothyroidism in a population-based cohort of pregnant women from North India","fulltext":[{"header":"Background","content":"\u003cp\u003eThe thyroid gland plays a key role in pregnancy homeostasis and metabolic adaptations important for fetal development, as well as supply of energy to the mother. It undergoes adaptive changes to meet the increased demand during pregnancy, and women with low reserves during preconception frequently enter pregnancy in hypothyroid state. Hypothyroidism is the commonest endocrine disorder of pregnancy, and if not adequately treated, can result in adverse pregnancy outcomes- growth restriction, prematurity, low birth weight (LBW) and stillbirth (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). However, the symptoms are nonspecific and insidious; hence, diagnosis is usually missed or made much later due to delayed reporting of pregnancy (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGlobally, hypothyroidism affects 3\u0026ndash;5% of all pregnant women, however, the prevalence is higher in Asian countries (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In a Chinese study of 2899 pregnant women, the prevalence of hypothyroidism (TSH\u0026thinsp;\u0026gt;\u0026thinsp;3.93 mIU/L) in the first trimester was 10.9% (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Yadav et al, in a meta-analysis of observational studies, reported a pooled prevalence of 11.01% in pregnant women in India (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e), however, only two of the 54 studies were community based, and the cut off levels of TSH used were not uniform, varying from 2.3\u0026ndash;4.5 mIU/mL in all three trimesters of pregnancy. Data from secondary and tertiary hospital across nine states in India showed 13.1% prevalence in the first trimester, with a TSH cutoff of 4.5 mIU/mL (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe thyroid stimulating hormone (TSH) assay is a simple, sensitive, commonly used screening tool for thyroid dysfunction in pregnancy but is limited by lack of uniformly accepted reference ranges which vary according to laboratory reference levels, type of assay, and population heterogeneity. The new third generation assays have high functional sensitivity as recommended by the American Thyroid Association (ATA) and are a good tool for diagnosing primary thyroid dysfunction (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The National Guidelines in India (2014) recommend treatment aimed at maintenance of TSH\u0026thinsp;\u0026lt;\u0026thinsp;2.5 mIU/mL in the first trimester and \u0026lt;\u0026thinsp;3 mIU/mL in the second and third trimester of pregnancy, similar to the guidelines of the Endocrine Society (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). The ATA 2017 recommends 4 mIU/mL as the upper limit of normal, in the absence of population specific ranges (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). A systematic review of normative values of trimester specific thyroid function in Indian women concluded that TSH cut offs of up to 5\u0026ndash;6 mIU/mL, similar to the pre-pregnancy stage, should be used in the first trimester of pregnancy, although it was limited by the fact that no outcomes were included (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere are limited data on population-based prevalence, risk factors and adverse outcomes of hypothyroidism in pregnancy, particularly in low to mid socio-economic populations. We conducted an analysis of data from a population-based cohort of urban and peri-urban low-mid socioeconomic strata neighborhoods of Delhi to determine the prevalence of hypothyroidism in pregnancy, its risk factors, and impact of replacement on adverse pregnancy outcomes LBW, prematurity, small for gestational age (SGA), and stillbirth.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design, setting and participants\u003c/h2\u003e \u003cp\u003eThis is an observational study embedded within the intervention group of the Women and Infants Integrated Interventions for Growth Study (WINGS), conducted in urban and peri-urban low-to-mid-socioeconomic neighborhoods in south Delhi, India. A summary of WINGS is provided below; the details of methods have been previously published (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Briefly, 13,500, eligible women aged 18\u0026ndash;30 years were identified through a door-to-door survey. Women who provided written consent to participate in the study were enrolled (first randomization) to receive pre and peri-conception interventions or routine care and followed up until their pregnancies were confirmed, or for 18 months after enrollment. At confirmation of pregnancy by ultrasonography, after obtaining written consent a second randomization was done wherein pregnant women received enhanced pregnancy and early childhood care or routine care.\u003c/p\u003e \u003c/div\u003e\n\u003ch2\u003eStudy Description\u003c/h2\u003e\n\u003cp\u003ePregnant women in the intervention group received at least eight antenatal care visits. Body mass index (BMI) was measured, and a non-fasting serum TSH and hemoglobin tested at the time of confirmation of pregnancy. Women with TSH\u0026thinsp;\u0026ge;\u0026thinsp;2.5 mIU/mL were labelled as hypothyroid and were managed with replacement doses of levothyroxine, after a thorough history and clinical assessment as per the National Guidelines (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). TSH levels were repeated monthly, and thyroxine dose titrated till TSH stabilized to normal pregnancy reference levels (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Once normalized, a repeat TSH for monitoring, was done twice in the second trimester, and once in the late third trimester which amounted to an approximate five to six repeat assays of TSH in pregnancy. Close follow up was done by study team workers who made weekly home visits to ensure compliance, and progress was monitored using electronic trackers. Those with uncontrolled TSH and TSH\u0026thinsp;\u0026lt;\u0026thinsp;0.1 mIU/mL were referred to the endocrinology clinic of the collaborating government tertiary care hospital (Safdarjung Hospital, New Delhi, India).\u003c/p\u003e\n\u003ch2\u003eLaboratory Analysis\u003c/h2\u003e\n\u003cp\u003eBlood samples for TSH assay were collected in serum separator tubes (SST), transported in cool boxes (4˚to 8˚C) to the field laboratory where centrifugation was done at ~\u0026thinsp;450 \u0026times; g at room temperature for 10 minutes, to separate serum and then transported to a NABH accredited study laboratory (Oncquest Laboratory) maintaining cold chain.\u003c/p\u003e \u003cp\u003eSerum TSH was analyzed using the Architect (Ci 8200 Abbott-Architect) TSH assay, a two-step immunoassay using chemiluminescent microparticle immunoassay (CMIA) technology with an inter-assay coefficient of variation (CV) of 20% which meets the requirements of a of third generation TSH assay. The Architect TSH assay has an analytical sensitivity of \u0026lt;\u0026thinsp;0.01 \u0026micro;IU/mL (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSociodemographic characteristics were reported as mean (SD), or proportions, as appropriate. We calculated incidence (95% confidence interval: CI) of hypothyroidism occurring at the time of pregnancy confirmation. Univariable and multivariable generalized linear model with binomial family and log link were performed to ascertain risk factors associated with hypothyroidism. We calculated unadjusted and adjusted risk ratios (RR) and their 95% CI for the association between hypothyroidism and adverse pregnancy outcomes (LBW, SGA, preterm birth, spontaneous preterm birth, stillbirth) using generalized linear model with binomial family and log link. The candidate variables were related to socio-demographic and nutritional status of the women; continuous (maternal age, hemoglobin and glycosylated hemoglobin (HbA1c) levels at the time of confirmation of pregnancy), and categorical (height (\u0026lt;\u0026thinsp;150 and \u0026ge;\u0026thinsp;150 cm), years of schooling\u0026thinsp;\u0026lt;\u0026thinsp;12 and \u0026ge;\u0026thinsp;12 years), early pregnancy (gestational age\u0026thinsp;\u0026le;\u0026thinsp;20 weeks), BMI, religion (Hindu and others), type of family (extended or joint, and nuclear), family with a below-poverty-line card, and family covered by health insurance scheme. All statistical analyses were performed using STATA version 16 (StataCorp, College Station, TX, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eIn this study 2317 women were followed up from pregnancy till delivery. The median (IQR) of gestational age at the time of recruitment was 9.5 (9.1\u0026ndash;11.0) weeks. Socioeconomic and clinical characteristics of enrolled women prior to pregnancy are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The study population was relatively young with a mean (SD) age of 23.8 (3.1) years, about half of them had education more than 12 years. Height was less than 150 cm in 34.1%; mean (SD) BMI was 22.2 (3.9) kg/m\u003csup\u003e2\u003c/sup\u003e; with dual burden of malnutrition: 15% women underweight and 24% women overweight or obese (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSociodemographic characteristics of pregnant women\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics of pregnant women\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEuthyroid\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1640\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHypothyroid\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;677\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years), mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23.7 (3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24.0 (3.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm), mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e152.4 (5.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e152.2 (5.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight\u0026thinsp;\u0026lt;\u0026thinsp;150 cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e543 (33.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e246 (36.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSchooling\u0026thinsp;\u0026ge;\u0026thinsp;12\u0026nbsp;year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e837 (51.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e332 (49.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHomemaker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1562 (95.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e644 (95.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly pregnancy BMI, mean (SD)\u003c/p\u003e \u003cp\u003eUnderweight (\u0026lt;\u0026thinsp;18.5 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003eOverweight or obesity (\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22.2 (3.9)\u003c/p\u003e \u003cp\u003e258 (15.7)\u003c/p\u003e \u003cp\u003e364 (22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22.9 (4.1)\u003c/p\u003e \u003cp\u003e91 (13.4)\u003c/p\u003e \u003cp\u003e192 (28.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHindu\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1340 (81.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e566 (83.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily had a below poverty line card\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55 (3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e23 (3.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily covered by a health insurance scheme\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e170 (10.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e78 (11.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJoint or extended family*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1079 (65.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e458 (67.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAll values are numbers (percentages) unless stated otherwise\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003e* Joint or extended family: Adult relatives other than the enrolled woman\u0026rsquo;s husband and children living together in a household\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the thyroid status of pregnant women at the time of confirmation of pregnancy, with 29.2% (95% CI: 27.4 to 31.1) having hypothyroidism (TSH\u0026thinsp;\u0026ge;\u0026thinsp;2.5 mIU/mL).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThyroid status at the time of confirmation of pregnancy\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH level\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003en(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMean (SD)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMedian (IQR)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;2317\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH\u0026thinsp;\u0026lt;\u0026thinsp;0.1 mIU/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 (2.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.1 to 3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.04 (0.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.04 (0.04 to 0.05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH 0.1 to \u0026lt;\u0026thinsp;2.5 mIU/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1576 (68.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.1 to 69.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.3 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.3 (0.8 to 1.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH\u0026thinsp;\u0026ge;\u0026thinsp;2.5 to \u0026lt;\u0026thinsp;10 mIU/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e652 (28.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.3 to 30.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.0 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.6 (3.0 to 4.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTSH\u0026thinsp;\u0026ge;\u0026thinsp;10 mIU/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.6 to 1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e51.9 (124.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15.4 (13.0 to 33.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the association between socioeconomic and clinical characteristics of women with hypothyroidism. Overweight or obesity in early pregnancy was associated with increased risk (adjusted RR 1.29, 95% CI 1.10 to 1.51) of hypothyroidism. Hemoglobin concentration was a protective factor (adjusted RR 0.93, 95% CI 0.88 to 0.98 for each g/dL) for hypothyroidism.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePotential risk factors for hypothyroidism in enrolled women\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRisk factors for hypothyroidism\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eUnadjusted RR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAdjusted RR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (per 1 year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.02 (1.00 to 1.04); p\u0026thinsp;=\u0026thinsp;0.046\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.01 (0.99 to 1.04); p\u0026thinsp;=\u0026thinsp;0.249\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (\u0026lt;\u0026thinsp;150 cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.10 (0.97 to 1.26); p\u0026thinsp;=\u0026thinsp;0.134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.07 (0.92 to 1.23); p\u0026thinsp;=\u0026thinsp;0.372\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSchooling\u0026thinsp;\u0026ge;\u0026thinsp;12\u0026nbsp;year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.94 (0.83 to 1.07); p\u0026thinsp;=\u0026thinsp;0.382\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.93 (0.80 to 1.07); p\u0026thinsp;=\u0026thinsp;0.307\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHomemaker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.98 (0.73 to 1.31); p\u0026thinsp;=\u0026thinsp;0.903\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.08 (0.76 to 1.53); p\u0026thinsp;=\u0026thinsp;0.670\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJoint or extended family\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.06 (0.93 to 1.22); p\u0026thinsp;=\u0026thinsp;0.391\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.10 (0.95 to 1.28); p\u0026thinsp;=\u0026thinsp;0.231\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily had below-poverty-line card\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.01 (0.72 to 1.43); p\u0026thinsp;=\u0026thinsp;0.958\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.00 (0.69 to 1.46); p\u0026thinsp;=\u0026thinsp;0.990\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily covered by health insurance scheme\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.10 (0.90 to 1.32); p\u0026thinsp;=\u0026thinsp;0.407\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.06 (0.85 to 1.32); p\u0026thinsp;=\u0026thinsp;0.577\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHindu religion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.10 (0.92 to 1.31); p\u0026thinsp;=\u0026thinsp;0.283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.10 (0.91 to 1.33); p\u0026thinsp;=\u0026thinsp;0.341\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEarly pregnancy BMI\u003c/p\u003e \u003cp\u003eNormal BMI\u003c/p\u003e \u003cp\u003eUnderweight (\u0026lt;\u0026thinsp;18.5 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003cp\u003eOverweight or obesity (\u0026ge;\u0026thinsp;25 kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.93 (0.77 to 1.13); p\u0026thinsp;=\u0026thinsp;0.497\u003c/p\u003e \u003cp\u003e1.24 (1.07 to 1.43); p\u0026thinsp;=\u0026thinsp;0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003cp\u003e0.97 (0.78 to 1.20); p\u0026thinsp;=\u0026thinsp;0.783\u003c/p\u003e \u003cp\u003e1.29 (1.10 to 1.51); p\u0026thinsp;=\u0026thinsp;0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin at pregnancy confirmation\u003c/p\u003e \u003cp\u003e(per 1 percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.96 (0.91 to 1.01): p\u0026thinsp;=\u0026thinsp;0.114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.93 (0.88 to 0.98): p\u0026thinsp;=\u0026thinsp;0.009\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c (%) at pregnancy confirmation\u003c/p\u003e \u003cp\u003e(per 1 percentage)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.96 (0.80 to 1.15); p\u0026thinsp;=\u0026thinsp;0.644\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.92 (0.77 to 1.10); p\u0026thinsp;=\u0026thinsp;0.363\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the association of hypothyroidism with adverse pregnancy outcomes where management of hypothyroidism was supported by the research team. We found no significant association of hypothyroidism with LBW, SGA, preterm, spontaneous preterm birth and stillbirth.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociation between hypothyroidism and adverse pregnancy outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo hypothyroid\u003c/p\u003e \u003cp\u003en(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHypothyroid\u003c/p\u003e \u003cp\u003en(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eUnadjusted RR\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAdjusted RR*\u003c/p\u003e \u003cp\u003e(95% CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLow birth weight\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1388\u003c/p\u003e \u003cp\u003e326 (23.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;560\u003c/p\u003e \u003cp\u003e142 (25.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003cp\u003e(0.91 to 1.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.08\u003c/p\u003e \u003cp\u003e(0.91 to 1.28)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmall for gestational age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1382\u003c/p\u003e \u003cp\u003e370 (26.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;554\u003c/p\u003e \u003cp\u003e176 (31.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.19\u003c/p\u003e \u003cp\u003e(1.02 to 1.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.20\u003c/p\u003e \u003cp\u003e(1.00 to 1.44)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreterm birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1592\u003c/p\u003e \u003cp\u003e202 (12.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;649\u003c/p\u003e \u003cp\u003e76 (11.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.92\u003c/p\u003e \u003cp\u003e(0.72 to 1.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003cp\u003e(0.71 to 1.16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpontaneous preterm birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1592\u003c/p\u003e \u003cp\u003e122 (7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;649\u003c/p\u003e \u003cp\u003e38 (5.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003cp\u003e(0.54 to 1.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.76\u003c/p\u003e \u003cp\u003e(0.54 to 1.09)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStillbirth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;1603\u003c/p\u003e \u003cp\u003e22 (1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;659\u003c/p\u003e \u003cp\u003e14 (2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.55\u003c/p\u003e \u003cp\u003e(0.80 to 3.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.53\u003c/p\u003e \u003cp\u003e(0.79 to 2.98)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*adjusted for maternal age, height, years of schooling, early pregnancy (gestational age\u0026thinsp;\u0026le;\u0026thinsp;20 weeks), BMI\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe main findings of this study were the high prevalence of hypothyroidism in early pregnancy, occurring in 29.2% of the population-based cohort and that treating hypothyroidism early and adequately did not no increase in adverse outcomes (stillbirth, preterm birth, LBW, SGA). Anemia, overweight and obesity in early pregnancy were identified as risk factors for hypothyroidism.\u003c/p\u003e \u003cp\u003eA wide disparity in the prevalence of hypothyroidism in pregnancy has been reported in previous studies in India. A hospital-based study from nine states of India reported 15% prevalence of hypothyroidism using TSH levels of \u0026gt;\u0026thinsp;4.5 mIU/mL and of 44.3% using a cut off level of \u0026gt;\u0026thinsp;2.5 mIU/mL in first trimester (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). A meta-analysis of observational studies with varying gestational ages and TSH cut off values found the prevalence of hypothyroidism in pregnancy to be 11% (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). A prospective observational study from central part of India found hypothyroidism in 9.1% in the third trimester of pregnancy using a cut off of TSH\u0026thinsp;\u0026gt;\u0026thinsp;5 mIU/mL. Similar to our study, Bein et al in a systemic review and metaanlysis reported a decrease in risk of pregnancy loss and neonatal death with treatment of subclinical hypothyroidism (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSimilar to our finding, a study from southern part of India showed overweight or obesity was a risk factor for hypothyroidism in early pregnancy, and high maternal TSH is associated with obesity and higher weight gain (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The association of obesity and overweight with adverse outcomes is well documented including a recent systemic review and metaanalysis (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Similarly, our finding of a higher hemoglobin level being protective was echoed in a systemic review and meta analysis which found that iron deficiency adversely affects thyroid function and autoimmunity in pregnant women (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Also, a study from China found that proportion of hypothyroidism was higher in women with mild anemia in the first trimester than in women with no anemia (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe strengths of our study are that it is population-based; the socioeconomic strata is low to middle income, which represents the average Indian population; serum TSH was used for thyroid status assessment, which is feasible as a screening test in settings like India where pregnant women may not return after the first visit due to economic reasons, lack of easy accessibility to the health center, etc., and the evidence that early identification and adequate treatment, reduced the risk of adverse pregnancy outcomes. The limitations of our study are that we did not test for other thyroid hormones (T4, T3, Free T4, Free T3), so we could not distinguish subclinical from overt hypothyroidism; nor did we test for thyroid antibodies, which could have helped us detect \u0026ldquo;at risk\u0026rdquo; pregnancies.\u003c/p\u003e \u003cp\u003eThis study has important implications for health care of women of the reproductive age group. First, the high burden of hypothyroidism in early pregnancy and the prevention of adverse pregnancy outcomes with early management highlights the need for early detection and treatment in antenatal care programs. Secondly, preventive interventions could be introduced preconceptionally to reduce risk factors, like obesity and overweight, and low hemoglobin levels.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eAlmost a third of women from a mid-low socio-economic population may be at risk for developing hypothyroidism in early pregnancy. Anemia, being overweight or obese may increase the risk. Ensuring universal TSH screening in early pregnancy, and adequate treatment if hypothyroidism is detected, would serve to improve pregnancy outcomes. Reducing pre and periconception obesity and anemia could help reduce the risk of hypothyroidism.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCI: confidence interval; ARR: adjusted relative risk; BMI: body mass index; LBW: low birth weight; SGA: small for gestational age; TSH: thyroid stimulating hormone; WINGS: women and Infants integrated interventions for growth study; ATA: american thyroid association ; SST: serum separator tubes; \u003cem\u003eCMIA:\u0026nbsp;\u003c/em\u003echemiluminescent microparticle immunoassay; CV: coefficient of variation; RR: risk ratios\u003c/p\u003e\n"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Ethics Review Committees of the Society for Applied Studies, Vardhman Mahavir Medical College and Safdarjung Hospital, and the World Health Organization, Geneva approved the study conducted with the relevant guidelines and regulations (e.g. Declaration of Helsinki). Written informed consent was obtained from the study participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe dataset analyzed during the current study are not publicly available because Society for Applied Studies, India is a collaborator in the Healthy Birth, Growth, and Development Knowledge Integration (HBGDKi) initiative launched by the Bill \u0026amp; Melinda Gates Foundation. However, individual requests can be considered on a case-by-case basis. The request for data along with the detailed proposal describing the intended scientific question (s) to be addressed, should be submitted to Dr. Sunita Taneja ([email protected] ).\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe main trial was funded by the Biotechnology Industry Research Assistance Council (BIRAC), Department of Biotechnology, Government of India under the Grand Challenges India- All Children Thriving Initiative (GCIACT Ref No: BIRAC/GCI/0085/03/14-ACT) and the Bill \u0026amp; Melinda Gates Foundation, USA (Grant ID #OPP1191052). The funding agencies did not play any role in study design and are neither involved in nor have any influence over the collection, analyses or interpretation of data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eND, RaC, NB, AV, ST were involved in conceptualizing the research questions, data file preparation, statistical analysis, data interpretation, writing and editing of manuscript. RiC, PM, RD, JK critically revised the manuscript for relevant intellectual content. All authors contributed to preparation and finalization of the manuscript and have read and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe The Society for Applied Studies gratefully acknowledges the contribution and support of the mothers, their families and others in the community.\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eWe acknowledge the core support provided by the Department of Maternal, Newborn, Child and Adolescent Health, World Health Organization, Geneva (WHO Collaborating Centre IND-158).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eMahadik K, Choudhary P, Roy PK. Study of thyroid function in pregnancy, its feto-maternal outcome; a prospective observational study. BMC pregnancy and childbirth. 2020;20(1):769.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCunningham FG, Leveno KJ, Bloom SL, Dashe JS, Hoffman BL, Casey BM, et al. Overview of Obstetrics. Williams Obstetrics, 25e. New York, NY: McGraw-Hill Education; 2018.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWarri D, George A. Perceptions of pregnant women of reasons for late initiation of antenatal care: a qualitative interview study. BMC pregnancy and childbirth. 2020;20(1):70.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eTeng W, Shan Z, Patil-Sisodia K, Cooper DS. Hypothyroidism in pregnancy. The lancet Diabetes \u0026amp; endocrinology. 2013;1(3):228\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eWang W, Teng W, Shan Z, Wang S, Li J, Zhu L, et al. The prevalence of thyroid disorders during early pregnancy in China: the benefits of universal screening in the first trimester of pregnancy. European journal of endocrinology. 2011;164(2):263\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eYadav V, Dabar D, Goel AD, Bairwa M, Sood A, Prasad P, et al. Prevalence of Hypothyroidism in Pregnant Women in India: A Meta-Analysis of Observational Studies. Journal of thyroid research. 2021;2021:5515831.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDhanwal DK, Bajaj S, Rajput R, Subramaniam KA, Chowdhury S, Bhandari R, et al. Prevalence of hypothyroidism in pregnancy: An epidemiological study from 11 cities in 9 states of India. Indian journal of endocrinology and metabolism. 2016;20(3):387\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAw T, Sickan J, Du S, Li J, Janel H. Reference Intervals for TSH on the Architect Analyser Based on the National Academy of Clinical Biochemistry (NACB) Guidelines Derived from Healthy Multi-Ethnic Asians Attending a Community Health Fair. Int Arch Endocrinol Clin Res. 2019;5:015.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eIndia MHDMoHFWGo. National Guidelines for Screening of Hypothyroidism during Pregnancy, India. 2014.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eDe Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. The Journal of clinical endocrinology and metabolism. 2012;97(8):2543\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eAlexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid: official journal of the American Thyroid Association. 2017;27(3):315\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eKannan S, Mahadevan S, Sigamani A. A Systematic Review on Normative Values of Trimester-specific Thyroid Function Tests in Indian Women. Indian journal of endocrinology and metabolism. 2018;22(1):7\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eTaneja S, Chowdhury R, Dhabhai N, Mazumder S, Upadhyay RP, Sharma S, et al. Impact of an integrated nutrition, health, water sanitation and hygiene, psychosocial care and support intervention package delivered during the pre- and peri-conception period and/or during pregnancy and early childhood on linear growth of infants in the first two years of life, birth outcomes and nutritional status of mothers: study protocol of a factorial, individually randomized controlled trial in India. Trials. 2020;21(1):127.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSarkar R. TSH Comparison Between Chemiluminescence (Architect) and Electrochemiluminescence (Cobas) Immunoassays: An Indian Population Perspective. Indian journal of clinical biochemistry: IJCB. 2014;29(2):189\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eBein M, Yu OHY, Grandi SM, Frati FYE, Kandil I, Filion KB. Levothyroxine and the risk of adverse pregnancy outcomes in women with subclinical hypothyroidism: a systematic review and meta-analysis. BMC endocrine disorders. 2021;21(1):34.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eFallatah AM, Hasanain A, Babatin H, Nassibi KM, Thigah S, Abduljabbar HS. Pregnancy Outcomes among Obese Pregnant Women with Hypothyroidism: Medical Record Review of a Single Tertiary Center in Saudi Arabia. Cureus. 2020;12(2):e6938.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eCollares FM, Korevaar TIM, Hofman A, Steegers EAP, Peeters RP, Jaddoe VWV, et al. Maternal thyroid function, prepregnancy obesity and gestational weight gain-The Generation R Study: A prospective cohort study. Clinical endocrinology. 2017;87(6):799\u0026ndash;806.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eSong RH, Wang B, Yao QM, Li Q, Jia X, Zhang JA. The Impact of Obesity on Thyroid Autoimmunity and Dysfunction: A Systematic Review and Meta-Analysis. Frontiers in immunology. 2019;10:2349.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003ePillai NS, Bennett J. Prevalence of hypothyroidism amongst pregnant women: a study done in rural set up. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2018;7(4):1586\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eLuo J, Wang X, Yuan L, Guo L. Iron Deficiency, a Risk Factor of Thyroid Disorders in Reproductive-Age and Pregnant Women: A Systematic Review and Meta-Analysis. Frontiers in endocrinology. 2021;12:629831.\u003c/span\u003e\u003c/li\u003e\n \u003cli\u003e\u003cspan\u003eNie GY, Wang R, Liu P, Li M, Sun DJ. Mild Anemia May Affect Thyroid Function in Pregnant Chinese Women During the First Trimester. Frontiers in endocrinology. 2021;12:772917.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hypothyroidism, Low birth weight, Preterm, Small for gestational age ","lastPublishedDoi":"10.21203/rs.3.rs-1733985/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1733985/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003e\u003c/p\u003e\u003cp\u003eHypothyroidism is the commonest endocrine disorder of pregnancy, with known adverse feto-maternal outcomes. There is limited data on population-based prevalence, risk factors and outcomes associated with treatment of hypothyroidism in early pregnancy. We conducted analysis on data from an urban and peri-urban low to mid socioeconomic population-based cohort of pregnant women in North Delhi, India to ascertain \u0026nbsp;\u0026nbsp;the burden, risk factors and impact of treatment, on adverse pregnancy outcomes- low birth weight, prematurity, small for gestational age and stillbirth.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eThis is an observational study embedded within the intervention group of the Women and Infants Integrated Interventions for Growth Study, an individually randomized factorial design trial. Thyroid stimulating hormone was tested in 2317 women in early (9-13 weeks) pregnancy, and thyroxin replacement started in those found hypothyroid (TSH ≥2.5mIU/mL). Univariable and multivariable generalized linear model with binomial family and log link were performed to ascertain risk factors associated with hypothyroidism and association between hypothyroidism and adverse pregnancy outcomes.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eOf 2317 women, 29.2% (95% CI: 27.4 to 31.1) had hypothyroidism and were started on thyroxin replacement with close monitoring. Overweight or obesity was associated with increased risk (adjusted RR 1.29, 95% CI 1.10 to 1.51), while higher hemoglobin concentration was protective (adjusted RR 0.93, 95% CI 0.88 to 0.98 for each g/dL) for hypothyroidism. Women with hypothyroidism, received appropriate treatment did not have an increase in adverse pregnancy outcomes.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eAlmost a third of women from low to mid socio-economic population had hypothyroidism in early pregnancy, more so if anemic and overweight or obese. With early screening and adequate replacement, adverse pregnancy outcomes may be avoided. These findings highlight the need in early pregnancy for universal TSH screening and adequate treatment of hypothyroidism; as well as for attempts to reduce pre and peri-conception overweight, obesity and anemia. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eClinical Trial registration: \u003c/strong\u003eClinical trial registration of Women and Infants Integrated Interventions for Growth Study\u003cstrong\u003e \u003c/strong\u003eClinical Trial Registry – India, #CTRI/2017/06/008908; Registered on: 23/06/2017, (http://ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=19339\u0026amp;EncHid=\u0026amp;userName=society%20for%20applied%20studies)\u003c/p\u003e","manuscriptTitle":"Burden, risk factors and outcomes associated with adequately treated hypothyroidism in a population-based cohort of pregnant women from North India","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-06-22 19:28:09","doi":"10.21203/rs.3.rs-1733985/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"eb25bcbe-2216-4317-b257-1f67595fbbe6","owner":[],"postedDate":"June 22nd, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-01-30T22:29:12+00:00","versionOfRecord":[],"versionCreatedAt":"2022-06-22 19:28:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1733985","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1733985","identity":"rs-1733985","version":["v1"]},"buildId":"_rKDHFSCF-2tw6eG1fWyD","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}